Diarrheal diseases are a major cause of morbidity and mortality in the developing world. Among the most frequent bacterial causes of diarrhea are enterotoxigenic. Escherichia coli (ETEC), Shigella species, and C. jejuni. Indeed, C. jejuni is estimated to cause 2.5 million cases of gastroenteritis annually in the United States and greater than 400 million cases worldwide. In developing countries, C. jejuni gastroenteritis is primarily a pediatric disease. The symptoms of C. jejuni gastroenteritis include diarrhea, abdominal pain, fever and sometimes vomiting. Stools usually contain mucus, fecal leukocytes and blood, although watery diarrhea is also observed. The disease is zoonotic, and wild and domesticated birds represent a major reservoir. C. jejuni is a major foodborne infection, most often being associated with contaminated poultry, but major outbreaks have been associated with water or raw milk contamination.
In addition to causing gastroenteritis, C. jejuni can also cause several undesirable post-infectious conditions, including inflammatory bowel syndrome, and a spondyloarthropathy known as Reiter's Syndrome. Moreover, recent studies have indicated an association between C. jejuni infections and malnutrition and growth stunting in young children in resource-limited settings.
Another possible debilitating complication of C. jejuni infection is the development of Guillain-Barré Syndrome (GBS), a post-infectious polyneuropathy that can result in paralysis (Allos, B. M., J. Infect. Dis 176 (Suppl 2):S125-128 (1997).) C. jejuni is one of a limited number of bacteria that can endogenously synthesize sialic acid, a nine carbon sugar that is found in mammalian cells. The association between C. jejuni and GBS is reportedly due to molecular mimicry between the sialic acid containing-outer core of the lipooligosaccharide (LOS) present in C. jejuni and human gangliosides (Moran, et al., J. Endotox. Res. 3: 521 (1996).) It is believed that antibodies generated by a human subject against the LOS cores of C. jejuni may cause an undesirable autoimmune response to neural tissue in the subject. Indeed, studies suggest that LOS synthesis in Campylobacter is controlled by a number of genes, including genes encoding enzymes involved in the biosynthesis of sialic acid. The sialic acid is then incorporated into LOS. This is consistent with the observed molecular mimicry of LOS and human gangliosides in GBS. (Aspinall, et al., Eur. J. Biochem., 213: 1029 (1993); Aspinall, et al., Infect. Immun. 62: 2122-2125 (1994); Aspinall, et al., Biochem 33: 241 (1994); Salloway et al., Infect. Immun., 64: 2945 (1996).)
C. jejuni is a Gram-negative bacterium, having surface capsular polysaccharides (CPSs) that are involved in colonization and invasion and against which serum antibodies are generated. Recent analysis of the Campylobacter genome sequence has resulted in the identification of a complete set of capsule transport genes similar to those seen in type II/III capsule loci in the Enterobactericeae (Parkhill et al., Nature, 403: 665 (2000); Karlyshev et al., Mol. Microbiol., 35: 529 (2000).) Subsequent genetic studies in which site-specific mutations were made in several capsule transport genes indicate that the capsule is the major serodeterminant of the Penner serotyping scheme (Karlyshev et al., Mol. Microbiol., 35: 529 (2000).) The Penner scheme is one of two major serotyping schemes of campylobacters and was originally thought to be based on lipopolysaccharide O side chains (Moran and Penner, J. Appl. Microbiol., 86:361 (1999).) It is now believed that the structures previously described as O side chains are, in fact, polysaccharide capsules. Interestingly, although C. jejuni capsular moieties are important in serodetermination, and despite over 47 Penner serotypes of C. jejuni having been identified, it is believed that most Campylobacter diarrheal disease is caused by only a limited number of these serotypes. Therefore, only selected strains of C. jejuni, predicated on epidemiological studies, may provide suitable candidate strains for development of potential vaccine compositions.
Several immunogenic CPS-CRM197 conjugates associated with prevalent C. jejuni serotypes have been created. (Monteiro et al., (2009) Infect. Immun. 77, 1128-1136; Bertolo, L, et al. (2012) Carbohy Res 366:45-49.) An immunogenic C. jejuni CPS conjugate vaccine capable of protecting non-human primates against C. jejuni diarrhea has been developed. (Monteiro et al., (2009) Infect. Immun. 77, 1128-1136, U.S. Pat. No. 9,084,809.) U.S. Pat. No. 9,084,809 describes, inter alia, an anti-C. jejuni immunogenic composition composed of a capsule polysaccharide polymer of C. jejuni strain 81-176 (also referred to herein as serotype HS23/36) that is capable of inducing an immune response in BALB/c mice. This reference teaches that the HS23/36 capsule polysaccharide comprises trisaccharides of galactose, 3-O-methyl-6-deoxy-altro-heptose and N-acetyl glucosamine; specifically, the immunogenic polysaccharide polymer comprises a repeating trisaccharide structure having the formula [→3)-α-D-Gal-(1→2)-6d-3-O-Me-α-D-altro-Hep-(1→3)-β-D-GlcNAc-(1→] containing an O-methyl-phosphoramidate at the O-2 position of Gal. Notwithstanding the promise of prototype vaccines, and despite the importance of this organism to human disease, there are yet no licensed, commercially available vaccines against C. jejuni. Thus, there currently remains a need for improved immunogenic compositions and methods for preventing or ameliorating diseases associated with C. jejuni infection.